1. Field of the Invention
The invention relates to a process for preparing polycyclic xanthine phosphodiesterase V (“PDE V”) inhibitors. The invention further relates to compounds useful for preparing PDE V inhibitors.
2. Background
Processes for preparing PDE V inhibitor compounds can be found in U.S. Pat. Nos. 6,207,829, 6,066,735, 5,955,611, 5,939,419, 5,393,755, 5,409,934, 5,470,579, 5,250,534, WO 02/24698, WO 99/24433, WO 93/23401, WO 92/05176, WO 92/05175, EP 740,668 and EP 702,555. One type of PDE V inhibitor compound contains a xanthine functionality in its structure. Xanthines can be prepared as described by Peter K. Bridson and Xiaodong Wang in 1-Substituted Xanthines, Synthesis, 855 (July, 1995), which is incorporated herein by reference in its entirety. WO 02/24698, which is incorporated herein by reference in its entirety, teaches a class of xanthine PDE V inhibitor compounds useful for the treatment of impotence. A general process disclosed therein for preparing xanthine PDE V inhibitor compounds having the formula (I) follows:
                (i) reacting a compound having the formula (III) with an alkyl halide in the presence of a base (introduction of RII or a protected form of RII);        (ii) (a) debenzylating and then (b) alkylating the compound resulting from step (i) with an alkyl halide, XCH2RIII;        (iii) (a) deprotonating and then (b) halogenating the compound resulting from step (ii);        (iv) reacting the compound resulting from step (iii) with an amine having the formula RIVNH2; and        (v) removing a protecting portion of RII, if present, on the compound resulting from step (iv) to form the compound having the formula (I).        
RI, RII, RIII and RIV correspond to R1, R2, R3 and R4, respectively, in WO 02/24698, and are defined therein. WO 02/24698 (pages 44 and 68–73) also teaches a synthesis for the following xanthine compound (identified therein as Compound 13 or Compound 114 of Table II): 1-ethyl-3,7-dihydro-8-[(1R,2R)-(hydroxycyclopentyl)amino]-3-(2-hydroxyethyl)-7-[(3-bromo-4-methoxyphenyl)methyl]-1H-purine-2,6-dione:

It would be beneficial to provide an improved process for preparing polycyclic xanthine PDE V inhibitor compounds. It would further be beneficial if the process provided high yields without the need for chromatographic purification. It would still further be beneficial if the process provided compounds of high thermodynamic stability. It would be still further beneficial to provide intermediate compounds that can be used in the improved process. The invention seeks to provide these and other benefits, which will become apparent as the description progresses.